The long-term objective of this ongoing work is to improve our suboptimal therapy for systemic fungal infections through a better understanding of the actions and interaction among antimycotic agents. Recently, we have made important observations on synergistic combinations of imidazole antifungals, such as ketoconazole, and other agents which inhibit sterol synthesis. The major thrust of this proposal is to determine the effect of sterol synthesis inhibitors singly and in combinations on fungi and mammalian systems; the results should define the potential therapeutic efficacy and toxicity of the drugs. To accomplish our goals we also must develop better methods to evaluate sterol synthesis inhibition and growth inhibitory drug concentrations in fungi and to assess the effect of sterol synthesis inhibitors on de novo sterol synthesis in man. Our specific aims include: 1. Systematic evaluation of the potency and spectrum of antifungal action of combinations of ketocanazole with the many other agents that inhibit sterol synthesis, using standard evaluation methods and searching for better ones. 2. Development of a reliable test system to assess the antifungal activity of ketoconazole and ketoconazole combinations based on perturbations in the ergosterol biosynthetic pathway. Preliminary studies of a color test have been extremely encouraging. 3. Elucidation of the mechanisms of resistance in ketoconazole-resistant fungi. There are many ketoconazole-resistant fungi and the mechanism of resistance is unknown. 4. Determination of a convenient system with which to assess the effect of a sterol inhibitor(s) on de novo sterol synthesis in man in vivo. As important by-products of the work we expect to understand better the controls of sterol synthesis in fungus and man and the consequences (toxicities) of inhibition of sterol synthesis.